This investigation will explore the role of antibodies (Ab) in Dengue virus (DENV) pathogenesis using a two- part hypothesis-driven approach to studying antibody-dependent enhancement (ADE) of DENV infection and elucidating the immunopathological mechanisms responsible for vascular leakage in vitro and in vivo. Part one examines the ability of human monoclonal antibodies (HMAb) to enhance endothelial cell (EC) infectivity in vitro. We hypothesize that DENV-specific Abs can enhance infection of ECs leading to increased loss of EC barrier function and changes in vascular permeability. HMAbs generated from previously DENV-infected patients that exhibit ADE in vitro will be used to determine the ability of Abs to enhance DENV infection of ECs, resulting in disruption of vascular integrity in vitro. The second component involves the ability of HMAbs to cause ADE of DENV infection in vivo using the ferret as a novel small animal model of DENV infection. Our hypothesis is that in vitro EC infection correlates with in vivo pathology seen in DENV infection, specifically that the presence of Ab enhances EC infectivity and induces histopathological changes in the microvasculature resulting in vascular leak. Ferrets that are either mock treated or treated with HMAbs will subsequently be challenged with DENV and assessed for signs of enhanced infection, including clinical manifestations, increased viremia, and signs of vascular leakage. Results of these studies will determine the precise role of Abs in DENV pathogenesis, specifically their ability to induce vascular leak in vitro and in vivo, and will provide a clearer understanding of the role of DENV Abs in the induction of Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS).